The present invention relates to novel radicicol derivatives or pharmacologically acceptable salts thereof which show tyrosine kinase inhibition activity and have antitumor or immunosuppression effects.
It is known that microbial metabolite radicicol represented by the following formula (B) has an antifungal effect and an anticancer effect [Nature, 171, 344 (1953); Neoplasma, 24, 21 (1977) ], an immunosuppression effect (Japanese Published Unexamined Patent Application No. 298764/94), or morphology normalization effect of ras or mos canceration cells [Oncogene, 11, 161 (1995)]. 
Furthermore, it is known that radicicol derivatives in which the phenolic hydroxyl group is modified with various acyl groups have an antitumor effect (Japanese Published Unexamined Patent Application No. 226991/92). In addition, it is disclosed that radicicol derivatives in which the phenolic hydroxyl group is modified with an acyl group or an alkyl group show an angiogenesis inhibition effect (Japanese Published Unexamined Patent Application No. 279279/94) or an interleukin 1 production inhibition effect (Japanese Published Unexamined Patent Application No. 40893/96) Recently, oxime derivatives of dienone of a radicicol derivative showing antitumor action and immunosuppression action have been published (WO 96/33989: published on Oct. 31, 1996), and antitumor radicicol derivatives represented by the following formula (Bxe2x80x2) have also been published (Japanese Published Unexamined Patent Application 202781/97: published on Aug. 5, 1997). 
(In the formula, R1p and R2p represent a hydrogen atom or an acyl group; and Xp represents a halogen atom, a hydroxyl group or a lower alkoxy group.)
Additionally, it is known that ansamycins antibiotics, geldanamycin, represented by formula (C) [The Journal of Antibiotics, 23, 442 (1970)] has tyrosine kinase inhibition activity and antitumor effects [for example, Cancer Research, 52, 1721 (1992) and Cancer Research, 54, 2724 (1994)]. It is shown that these effects are expressed by the inhibition of the activation of a tyrosine kinase, such as Src, ErbB-2, Lck or the like, and a serine/threonine kinase Raf-1, through the formation of a complex of geldanamycin with a molecular chaperone Hsp (heat shock/stress protein) 90 by binding to Hsp90 [for example, Proceedings of the National Academy of Sciences of the U.S.A, 91, 8324 (1994) and The Journal of Biological Chemistry, 270, 24585 (1995)]. Consequently, drugs capable of acting upon Hsp90 are also included in tyrosine kinase inhibitors and useful not only as antitumor agents but also for the prevention and treatment of various diseases such as osteoporosis, immune diseases, and the like. 
Tyrosine kinase is an enzyme which uses ATP as a phosphate donor and catalyzes transfer of its xcex3-phosphate group to the hydroxyl group of a specified tyrosine residue of a substrate protein, thereby taking an important role in the control mechanism of intracellular signal transduction. Various tyrosine kinase families are known. Tyrosine kinase activities, such as Src in colon cancer, ErbB-2 in breast cancer and gastric cancer, Abl in leukemia, and the like, increase. Disordered increase in the tyrosine kinase activity causes abnormal differentiation and proliferation of cells. Consequently, specific inhibitors of tyrosine kinase are useful in preventing and treating various diseases, including as antitumor agents.
Lck is a tyrosine kinase which is activated when T lymphocytes are activated by antigen stimulation, and an inhibitor of this enzyme is useful as an immunosuppressant. Also, it is known that Src relates to bone resorption in osteoclast, and an inhibitor of this tyrosine kinase is useful as a bone resorption inhibitor for the treatment of osteoporosis. Additionally, inhibitors of receptor type tyrosine kinases of various growth factors, such as FGF-R (epidermal growth factor receptor), FGF-R (fibroblast growth factor receptor), PDGF-R (platelet-derived growth factor receptor), and the like, are useful as a solid cancer growth inhibitor, an angiogenesis inhibitor, a vascular smooth muscle growth inhibitor, and the like.
An object of the present invention is to provide novel radicicol derivatives or pharmacologically acceptable salts thereof which show tyrosine kinase inhibition activity and have antitumor or immunosuppression effects.
The present invention can provide radicicol derivatives represented by the following formula (I) or pharmacologically acceptable salts thereof: 
wherein R1 and R2 are the same or different, and each represents hydrogen, alkanoyl, alkenoyl, tert-butyldiphenylsilyl or tert-butyldimethylsilyl;
R3 represents:
Yxe2x80x94R5 {wherein Y represents substituted or unsubstituted alkylene; and R5 represents CONR6R7 (wherein R6 represents hydrogen, hydroxyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, or NR8R9 (wherein R8 and R9 are the same or different, and each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted alkanoyl, substituted or unsubstituted aroyl, carbonyl bound to a substituted or unsubstituted heterocyclic ring, or substituted or unsubstituted arylcarbamoyl), or is combined together with R7 and adjoining N to represent a substituted or unsubstituted heterocyclic group; and R7 is combined together with R6 and adjoining N to represent a substituted or unsubstituted heterocyclic group, or represents hydroxyl, substituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, or NR10R11 (wherein R10 and R11 have the same meaning as R8 and R9 defined above, respectively)), CO2R12 (wherein R12 represents substituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridonyl, substituted or unsubstituted pyrrolidonyl, substituted or unsubstituted uracilyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted morpholino, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted thiomorpholino, or substituted or unsubstituted dioxolanyl},
COR13 (wherein R13 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted aryl, substituted or unsubstituted lower alkoxy, or NR14R15 (wherein R14 and R15 are the same or different, and each represents hydrogen, substituted or unsubstituted-lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted pyridyl, or R14 and R15 are combined together with adjoining N to represent a substituted or unsubstituted heterocyclic group)), or
substituted or unsubstituted aryl;
X represents halogen, or is combined together with R4 to represent a single bond; and
R4 is combined together with X to represent a single bond, or represents hydrogen, alkanoyl, alkenoyl, or xe2x80x94SOxe2x80x94Z {wherein Z represents formula (A): 
wherein R1A and R2A have the same meaning as R1 and R2 defined above, respectively; XA represents halogen; and W represents O or Nxe2x80x94Oxe2x80x94R3A (wherein R3A has the same meaning as R3 defined above)}.
Hereinafter, the compound represented by formula (I) will be called compound (I). Compounds of other formula numbers with also be called in the same manner.
(1) Explanation of each group
In the definition of each group of compound (I), the term xe2x80x9clowerxe2x80x9d means 1 to 8 carbon atoms, and the term xe2x80x9chigherxe2x80x9d means 9 to 30 carbon atoms, unless otherwise indicated.
Examples of the alkanoyl include straight or branched groups having 1 to 30 carbon atoms, such as formyl, acetyl, propanoyl, isopropanoyl, butanoyl, caproyl, lauroyl, myristoyl, palmitoyl, stearoyl, and the like. Examples of the alkenoyl include straight or branched groups having 3 to 30 carbon atoms, such as acryloyl, methacryloyl, crotonoyl, isocrotonoyl, palmitoleoyl, linoleoyl, linolenoyl, and the like. Examples of the alkyl moiety of the lower alkyl and the lower alkoxy include straight or branched groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, isooctyl, and the like, and one of the carbon atoms thereof may be substituted with a silicon atom. Examples of the higher alkyl include straight or branched groups, such as decanyl, dodecyl, hexadecyl, and the like. Examples of the alkenyl include straight or branched groups having 2 to 30 carbon atoms, such as vinyl, allyl, 1-propenyl, 2-butenyl, 1-pentenyl, 2-hexenyl, 1, 3-pentadienyl, 1, 3-hexadienyl, dodecenyl, hexadecenyl, and the like. Examples of the lower cycloalkyl include groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like. Examples of the aryl include phenyl, naphthyl, and the like, and the aryl moiety of aroyl and arylcarbamoyl has the same meaning. Examples of the heterocyclic group include alicyclic heterocyclic groups, aromatic heterocyclic groups, and the like, such as pyridonyl, pyrrolidonyl, uracilyl, dioxolanyl, pyrrolyl, tetrazolyl, pyrrolidinyl, thienyl, morpholino, thiomorpholino, piperazinyl, pyrazolidinyl, piperidino, pyridyl, homopiperazinyl, pyrazolyl, pyrazinyl, indolyl, isoindolyl, furyl, piperidyl, quinolyl, phthalazinyl, imidazolidinyl, imidazolinyl, pyrimidinyl, and the like. The heterocyclic group moiety in the carbonyl bound to a heterocyclic ring has the same meaning as defined above, and examples of the entire group containing carbonyl include furoyl, thenoyl, nicotinoyl, isonicotinoyl, and the like. Examples of the nitrogen containing heterocyclic group formed by R6 and R7 with the adjoining N and the nitrogen containing heterocyclic group formed by R14 and R15 with the adjoining N (said heterocyclic group may further contain O, S or other N) include pyrrolidyl, morpholino, thiomorpholino, piperazinyl, pyrazolidinyl, pyrazolinyl, piperidino, homopiperazinyl, indolinyl, isoindolinyl, perhydroazepinyl, perhydroazocinyl, indolyl, isoindolyl, and the like. Examples of the alkylene include those groups in which one hydrogen atom is removed from the group of alkyl moiety of the above lower alkyl or higher alkyl. Examples of the halogen include fluorine, chlorine, bromine and iodine atoms.
(2) Explanation of substituent in each group
Examples of the substituent in the substituted lower alkyl, the substituted higher alkyl, the substituted alkenyl, the substituted lower alkoxy and the substituted alkanoyl include 1 to 3 substituents, which are the same or different, such as hydroxyl, lower cycloalkyl, lower cycloalkenyl, lower alkoxy, lower alkanoyloxy, azido, amino, mono- or di-lower alkylamino, mono- or di-lower alkanoylamino, lower alkoxycarbonylamino, lower alkenyloxycarbonylamino, halogen, lower alkanoyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, cyclic imido (a group formed by removing hydrogen bound to an imido N atom), CONR16R17 (wherein R16 and R17 are the same or different, and each represents hydrogen, hydroxyl, lower alkyl, lower cycloalkyl, higher alkyl, alkenyl, lower alkoxy, aryl, a heterocyclic group, or NR18R19 (wherein R18 and R19 are the same or different, and each represents hydrogen, lower alkyl, lower cycloalkyl, aryl, a heterocyclic group, lower alkanoyl, aroyl, carbonyl bound to a heterocyclic ring, or arylcarbamoyl)), CO2R20 (wherein R20 represents hydrogen, lower alkyl, higher alkyl, lower cycloalkyl, alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), or xe2x80x94(OCH2CH2)nOCH3 (wherein n is an integer of 1 to 10).
Examples of the substituent in the substituted alkylene include 1 to 3 substituents, which are the same or different, such as hydroxyl, lower alkoxy, lower alkanoyloxy, azido, amino, mono- or di-lower alkylamino, mono- or di-lower alkanoylamino, lower alkoxycarbonylamino, lower alkenyloxycarbonylamino, halogen, lower alkanoyl, substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridonyl, substituted or unsubstituted pyrrolidonyl, substituted or unsubstituted uracilyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted morpholino, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted thiomorpholino, substituted or unsubstituted dioxolanyl, cyclic imido (a group formed by removing hydrogen bound to an imido N atom), CONR16R17 (wherein R16 and R17 have the same meaning as defined above), or CO2R20 (wherein R20 has the same meaning as defined above).
Examples of the substituent in the substituted lower cycloalkyl, the substituted aryl, the substituted heterocyclic group, the substituted aroyl, the carbonyl bound to a substituted heterocyclic ring, the substituted arylcarbamoyl, the substituted pyridyl, the substituted pyridonyl, the substituted pyrrolidonyl, the substituted uracilyl, the substituted piperidyl, the substituted piperidino, the substituted pyrrolidinyl, the substituted morpholino, the substituted morpholinyl, the substituted piperazino, the substituted piperazinyl, the substituted thiomorpholino, the substituted dioxolanyl and the substituted nitrogen containing heterocyclic group formed with the adjoining N include 1 to 3 substituents, which are the same or different, such as hydroxyl, lower alkyl, lower alkyl substituted with a heterocyclic ring (said heterocyclic ring may be substituted with lower alkyl), higher alkyl, alkenyl, lower cycloalkyl, lower cycloalkenyl, lower alkoxy, lower alkoxy-lower alkoxy, lower alkanoyloxy, azido, amino, mono- or di-lower alkylamino, mono- or di-lower alkanoylamino, lower alkoxycarbonylamino, lower alkenyloxycarbonylamino, halogen, lower alkanoyl, aryl, a heterocyclic group, cyclic imido (a group formed by removing hydrogen bound to an imido N atom), CONR16R17 (wherein R16 and R17 have the same meaning as defined above), CO2R20 (wherein R20 has the same meaning as defined above), or SO2NR21R22 (wherein R21 and R22 are the same or different, and each represents hydrogen or lower alkyl) The lower alkyl, the higher alkyl, the alkenyl, the lower cycloalkyl, the lower alkoxy, the halogen, the aryl, the aroyl, the arylcarbamoyl, the heterocyclic group, and the carbonyl bound to a heterocyclic ring used herein have the same meaning as defined above. The lower alkyl moieties of the mono- or di-lower alkylamino, the lower alkoxycarbonyl, the lower alkoxycarbonylamino, and the lower alkoxy-lower alkoxy have the same meaning as defined above. The lower alkenyl moiety of the lower alkenyloxycarbonylamino means the above alkenyl group having 2 to 8 carbon atoms, such as vinyl, allyl, 1-propenyl, 2-butenyl, 1-pentenyl, 2-hexenyl, 1,3-pentadienyl, 1,3-hexadienyl, and the like. Examples of the lower cycloalkenyl include those having 4 to 8 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl, 1,3-cyclopentadienyl, and the like. Examples of the lower alkanoyl moiety of the lower alkanoyl, the lower alkanoyloxy and the mono- or di-lower alkanoylamino include straight or branched groups having 1 to 8 carbon atoms, such as formyl, acetyl, propanoyl, isopropanoyl, butanoyl, caproyl, and the like. Examples of the cyclic imido include phthalimido, succinimido, glutarimido, and the like.
As compound (I), compounds in which X is a halogen are preferred, and compounds in which X is combined together with R4 to represent a single bond are also preferred. Among the compounds in which X is combined together with R4 to represent a single bond, compounds in which R1 and R2 are hydrogen are preferred. Among these, compounds in which R3 (wherein R3 has the same meaning as defined above) is Yxe2x80x94R5 (wherein R5 has the same meaning as defined above) are more preferred. Among the compounds in which X is combined together with R4 to represent a single bond, compounds in which R1 and R2 are hydrogen, R3 is Yxe2x80x94R5 (wherein R5 has the same meaning as defined above) and R5 is substituted or unsubstituted aryl, and the like, are most preferred, and among these, compounds in which R5 is pyrrolidonyl are particularly preferred.
The pharmacologically acceptable salts of compound (I) include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Examples of the acid addition salts include inorganic acid salts (for example, hydrochloride, hydrobromide, sulfate, phosphate, and the like), and organic acid salts (for example, formate, acetate, oxalate, benzoate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, succinate, lactate, and the like). Examples of the metal salts include alkali metal salts (for example, lithium salt, sodium salt, potassium salt, and the like), alkaline earth metal salts (for example, magnesium salt, calcium salt, and the like), aluminum salts, zinc salts, and the like. Examples of the ammonium salts include salts with ammonium, tetramethylammonium, and the like. Examples of the organic amine addition salts include addition salts with morpholine, piperidine, and the like. Examples of the amino acid addition salts include addition salts with glycine, phenylalanine, aspartic acid, glutamic acid, lysine, and the like.
The compound of the present invention is generally prepared using radicicol as a starting material. Compound (I) may contain various stereoisomers, geometric isomers, tautomeric isomers, and the like. All of possible isomers and their mixtures are included in the present invention, and the mixing ratio is not particularly limited.
A production method of compound (I) is described below.
The production method of compound (I) mainly comprises oxime formation (production method 1), acylation/carbamoylation/alkoxycarbonylation (production method 2), alkylation (production method 3), amidation/esterification (production method 4), desilylation (production method 5), halohydrination (production method 6), silylation (production method 7), and acylation (production method 8), and each compound of interest is produced by combining these reaction steps depending on the object.
In the production methods shown below, when a defined group changes under conditions of the employed method or is not fit for carrying out the method, the compound of interest can be prepared using an introduction-elimination method of protecting groups usually used in synthetic organic chemistry [for example, see Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons Inc. (1981)]. As occasion demands, the sequence of reaction steps, such as introduction of substituent groups and the like, may be changed.
Production Method 1
Compound (Ia) can be prepared according to following reaction step, by oxime formation of the dienone carbonyl of radicicol, compound (D) which is prepared from radicicol by a known method (Japanese Published Unexamined Patent Application No. 226991/92) or compound (E) which is prepared from radicicol or a radicicol derivative in which one of the phenolic hydroxyl groups is substituted with alkanoyl or alkenoyl in accordance with a known method [for example, Journal of the American Chemical Society, 94, 6190 (1972)]. 
[In the above reaction formula, R1a and R2a represent groups in which tert-butyldimethylsilyl and tert-butyldiphenylsilyl are removed from R1 and R2 described above; R1b and R2b present groups in which at least one of R1 and R2 described above is substituted with tert-butyldimethylsilyl or tert-butyldiphenylsilyl; R3a is a group in which COR13 (wherein R13 has the same meaning as describe above) is removed from R3 described above; and R1 and R2 have the same meaning as defined above.]
Step 1
Compound (Ia) can be prepared by allowing compound (D) or compound (E) to react with compound (II) represented by the following formula H2Nxe2x80x94Oxe2x80x94R3a (II) (wherein R3a has the same meaning as defined above) or an acid addition salt thereof.
Examples of the reaction solvent include pyridine, chloroform, dichloromethane, ethyl acetate, ether, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, and the like, which may be used either alone or as a mixture thereof, and pyridine is preferred. Examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like, and they are preferably used in an amount of 0.1 to 10 equivalents based on compound (D) or (E). When an acid addition salt of compound (II) is used, the reaction can be carried out in the presence of a base, for example, amines (e.g., pyridine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, N,N-dimethylaniline, or the like) or alkali metal carbonate or bicarbonate (e.g., sodium carbonate, potassium carbonate, or the like), in an amount of 1 equivalent or more based on the acid addition salt of compound (II), preferably using pyridine which also serves as the solvent. The compound (II) or an acid addition salt thereof is used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on compound (D) or (E). The reaction is carried out at a temperature of xe2x88x9220 to 100xc2x0 C., preferably 20 to 60xc2x0 C., and the reaction completes after 1 to 80 hours.
Production Method 2
Compound (Ib) can be prepared by the steps in which compound (F) is converted into oxime compound (G), and then the resulting hydroxyl group is subjected to acylation, carbamoylation or alkoxycarbonylation. 
[In the above reaction formula, R1c and R2c are the same or different, and each represents alkanoyl, alkenoyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, and R3b represents COR13 (wherein R13 has the same meaning as defined above).]
Step 2-1
Compound (G) can be prepared by allowing compound (F) to react with hydroxylamine or an acid addition salt thereof according to method of the above step 1.
Step 2-2
Compound (Ib) can be prepared by allowing compound (G) to react with compound (III) represented by the following formula R13COCl (III) (wherein R13 has the same meaning as defined above), or with compound (IV) represented by the following formula R23NCO (IV) (wherein R23 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted pyridyl), in the presence of a base.
As the reaction solvent, dichloromethane, ether, THF, DMF, and the like, may be used alone or as a mixture thereof. As the base, amines (for example, pyridine, triethylamine, diisopropylethylamine, or the like) are used in an amount of 0.1 equivalent or more, preferably 1 to 10 equivalents, based on compound (III) or (IV). Compound (III) or (IV) is used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on compound (G) The reaction is carried out at a temperature of xe2x88x9280 to 100xc2x0 C., preferably xe2x88x9280 to 0xc2x0 C., when compound (III) is used, or at a temperature of 0 to 80xc2x0 C. when compound (IV) is used, and each reaction completes after 10 minutes to 48 hours.
Production Method 3
Compound (Ic) can be prepared by a step in which the hydroxyl group of the above compound (G) is alkylated. 
[In the above reaction formula, R3c represents Yxe2x80x94R5 (wherein Y and R5 have the same meaning as defined above), and R1c and R2c have the same meaning as defined above.]
Step 3
Compound (Ic) can he prepared by allowing compound (G) to react with compound (V) represented by the following formula HOR24 (V) (wherein R24 has the same meaning as R3c defined above) in the presence of a condensing agent.
As the reaction solvent, toluene, dichloromethane, and the like, are used alone or as a mixture thereof. As the condensing agent, trivalent phosphorous compounds (for example, triphenylphosphine, tributylphosphine, or the like) and azo compounds (for example, diethyl azodicarboxylate (DEAD), 1,1-(azodicarbonyl) dipiperidine, and the like) are used as a mixture thereof. Each of compound (V) and the condensing agent is used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on compound (G). The reaction is carried out at a temperature of xe2x88x9220 to 80xc2x0 C., preferably 0 to 30xc2x0 C., and the reaction completes after 5 minutes to 48 hours.
Production Method 4
Compound (Id) can be prepared by steps in which compound (E) is converted into oxime compound (J) in which a carboxyl group is introduced, and then the carboxyl group is subjected to amidation or esterification. 
{In the above reaction formula, R3d represents Yxe2x80x94R5a [wherein R5a represents CONR6R7 (wherein R6 and R7 have the same meaning as defined above) or CO2R12 (wherein R12 has the same meaning as defined above), and Y has the same meaning as defined above], and Y, R1 and R2 have the same meaning as defined above.}
Step 4-1
Compound (J) can be prepared by allowing compound (H) to react with compound (VI) represented by the following formula H2Nxe2x80x94Oxe2x80x94Yxe2x80x94CO2H (VI) (wherein Y has the same meaning as defined above) or an acid addition salt thereof according to the method of the above step 1.
Step 4-2
Compound (Id) can be prepared by allowing compound (J) to react with compound (VII) represented by the following formula HNR6R7 (VII) (wherein R6 and R7 have the same meaning as defined above) or an acid addition salt thereof, or with a compound (VIII) represented by the following formula HOR12 (VIII) (wherein R12 has the same meaning as defined above), in the presence of a condensing agent.
As the condensing agent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole, or the like, is used. Additionally, the reaction can be accelerated by adding an additive agent, such as N-hydroxysucciniimide (HONSu), 4-(dimethylamino)pyridine (DMAP), 1-hydroxybenzotriazole hydrate (HOBt), or the like, in an amount of 0.1 to 5 equivalents based on compound (J) As the reaction solvent, dichloromethane, ether, THF, DMF, and the like, may be used alone or as a mixture thereof. When an acid addition salt of compound (VII) is used, the reaction can be carried out in the presence of a base, such as amines (for example, pyridine, triethylamine, diisopropylethylamine, or the like), preferably triethylamine, in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, based on the acid addition salt of compound (VII). Each of compound (VII) or an acid addition salt thereof or compound (VIII) and the condensing agent is used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on compound (J) The reaction is carried out at a temperature of xe2x88x9220 to 80xc2x0 C., preferably 0 to 40xc2x0 C., and each reaction completes after 10 minutes to 48 hours.
Production Method 5
Compound (If) can be prepared by carrying out desilylation of compound (Ie) which is a derivative compound of (I) in which at least one of R1 and R2 is substituted with tert-butyldimethylsilyl or tert-butyldiphenylsilyl. 
(In the above reaction formula, R1b, R2b and R3 have the same meaning as defined above, and R1d and R2d are groups in which at least one of tert-butyldimethylsilyl or tert-butyldiphenylsilyl of the above R1b and R2b is substituted with hydrogen.)
Step 5
Compound (If) can be prepared by allowing compound (Ie) to react with a desilylation agent.
As the reaction solvent, THF, chloroform, dichloromethane, toluene, water, methanol, and the like may be used alone or as a mixture thereof. Examples of the desilylation agent include tetrabutylammonium fluoride (TBAF), sodium fluoride, hydrofluoric acid, and the like. The reaction may be carried out by increasing the reaction pH by adding an acid, such as acetic acid, hydrochloric acid or the like. The desilylation agent is used in an amount of 0.1 equivalent or more, preferably 1 to 10 equivalents, based on compound (Ie). The reaction is carried out at a temperature of xe2x88x9220 to 50xc2x0 C., and the reaction completes after 5 minutes to 24 hours.
Production Method 6
Compound (Ih) can be prepared by ring-opening the epoxide of compound (Ig) into a halohydrin or the like. 
[In the above reaction formula, R1a, R2a and R3 have the same meaning as defined above; Xa represents halogen; and R4a represents hydrogen, formyl, or xe2x80x94SOxe2x80x94Z (wherein Z has the same meaning as defined above).]
Step 6-1
A member of compound (Ih) in which R4a is hydrogen can be prepared by allowing compound (Ig) to react with an acid (for example, hydrogen chloride, hydrogen bromide, or the like) or a Lewis acid (for example, titanium tetrachloride, or the like).
As the solvent, dioxane, THF, ether, chloroform, dichloromethane, DMF, acetonitrile, methanol, ethyl acetate, and the like may be used either alone or as a mixture thereof. The acid or Lewis acid is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, based on compound (Ig). The reaction is carried out at a temperature of xe2x88x9220 to 40xc2x0 C., preferably 0 to 40xc2x0 C., and the reaction completes after 10 minutes to 48 hours.
Step 6-2
A member of compound (Ih) in which R4a is formyl can be prepared by allowing compound (Ig) to react with phosphorous oxychloride or phosphorous oxybromide in DMF. Phosphorous oxychloride or phosphorous oxybromide is used in an amount of 1 equivalent or more, preferably 2 to 5 equivalents, based on compound (Ig). The reaction is carried out at a temperature of xe2x88x9210 to 40xc2x0 C., preferably 0 to 40xc2x0 C., and the reaction completes after 1 to 48 hours.
Step 6-3
A dimer compound as a member of compound (Ih) in which R4a is xe2x80x94SOxe2x80x94Z (wherein Z has the same meaning as defined above) can be prepared by allowing compound (Ig) to react with thionyl chloride or thionyl bromide. As the solvent, DMF, chloroform, dichloromethane, dimethyl sulfoxide (DMSO), acetonitrile, and the like may be used either alone or as a mixture thereof. Thionyl chloride or thionyl bromide is used in an amount of 1 equivalent or more, preferably 2 to 10 equivalents, based on compound (Ig). The reaction is carried out at a temperature of xe2x88x9210 to 40xc2x0 C., preferably 0 to 40xc2x0 C., and the reaction completes after 1 to 48 hours.
Production Method 7
Compound (Ij) which is a derivative of compound (I) in which at least one of R1 and R2 is substituted with tert-butyldimethylsilyl or tert-butyldiphenylsilyl can be prepared from compound (Ii) by the following step. 
(In the above reaction formula, R3, R4, and X have the same meaning as defined above; R1e and R2e represent both hydrogen, or one represents hydrogen and the other represents alkanoyl or alkenoyl; and R1f and R2f represent groups in which at least one hydrogen of either of the above R1e and R2e is substituted with tert-butyldimethylsilyl or tert-butyldiphenylsilyl.)
Step 7
Compound (Ij) can be prepared by allowing compound (Ii) to react with tert-butyl(chloro)dimethylsilane or tert-butylchlorodiphenylsilane in the presence of a base.
As the solvent, chloroform, dichloromethane, ether, THF, acetone, DMF, acetonitrile, and the like are used either alone or a mixture thereof. As the base, amines (for example, pyridine, imidazole, triethylamine, diisopropylethylamine, or the like) are used. Tert-butyl(chloro)dimethylsilane or tert-butylchlorodiphenylsilane is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, based on compound (Ii). The base is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalent, based on tert-butyl(chloro)dimethylsilane or tert-butylchlorodiphenylsilane. The reaction is carried out at a temperature of xe2x88x9220 to 50xc2x0 C., preferably 10 to 40xc2x0 C., and the reaction completes after 10 minutes to 24 hours.
Production Method 8
Compound (Im) in which at least one hydrogen of any one of R1, R2 and R4 in compound (I) is substituted with alkanoyl or alkenoyl can be prepared by carrying out acylation of the following compound (Ik). 
(In the above reaction formula, R3 and X have the same meaning as defined above; at least one of R1g, R2g and R4b represents hydrogen; and R1h, R2h and R4c represent groups in which at least one hydrogen of the above R1g, R2g and R4b is substituted with alkanoyl or alkenoyl.)
Step 8
Compound (Im) can be prepared by allowing compound (Ik) to react with 1 equivalent or more, preferably 1 to 100 equivalents, of an acid halide, an acid anhydride, a mixed acid anhydride containing the alkanoyl or alkenoyl of interest, or the like, in the presence of a base.
As the solvent, DMF, DMSO, chloroform, dichloromethane, toluene, and the like may be used either alone or as a mixture thereof. An optional hydroxyl group can be modified by optionally carrying out introduction and elimination of a protecting group of the hydroxyl group, and it is possible to modify a plurality of hydroxyl groups at the same time. As the base, pyridine, triethylamine, N,N-dimethylaniline, N,N-dimethylaniline, or the like is used in an amount of 1 equivalent or more, preferably 1 to 200 equivalents, based on compound (Ik). It is possible to use a base (for example, pyridine, or the like) also as the solvent. Additionally, the reaction can be accelerated by adding DMAP or the like in an amount of 0.1 to 4 equivalents based on compound (Ik). The reaction is carried out at a temperature of xe2x88x9220 to 50xc2x0 C., and the reaction completes after 5 minutes to 24 hours.
In the production of compound (I), conversion of the functional group of R1, R2, R3, R4 or X can be carried out not only by the above steps but also by known methods [for example, Comprehensive Organic Transformations, R. C. Larock (1989)].
Isolation and purification of the products of the above methods can be carried out by carrying out optional combinations of techniques generally used in organic syntheses (e.g., filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like). The intermediates may be used in the subsequent reactions without purification.
If a salt of compound (I) is prepared, the salt of compound (I) can be purified as such when it can be prepared; or, when the compound is prepared in its free form, its salt can be formed by dissolving or suspending it in an appropriate solvent and adding an acid or base thereto.
Also, compound (I) or pharmacologically acceptable salts thereof may exist in the form of addition products with water or various solvents, and these addition products are also included in the present invention. Examples of compound (I) are shown in Table 1.
Next, pharmacological activities of typical examples of compound (I) are described by the following test examples.